CONSULT THE EXPERT h ENDOCRINOLOGY h PEER REVIEWED

Monitoring Blood Glucose in Patients with Diabetes Mellitus

Thomas Schermerhorn, VMD, DACVIM (SAIM) Kansas State University

A long-term patient monitoring strategy that is Optimal glycemic control requires appropriate clinically sound, practical, and effective should be insulin therapy to control hyperglycemia and avoid hypoglycemia and other complications. developed for every patient with diabetes mellitus Various laboratory tests and clinical tools are (DM). A close clinician–pet owner relationship is available and appropriate for monitoring 3,4 ; critical to success, as the pet owner provides daily however, no single method or combination has been shown to have clear, significant clini- care and performs most day-to-day monitoring. cal benefits. Therefore, the monitoring pro- Owners should be educated to recognize early signs of gram should be practical and the components problems with DM management and to communicate tailored to meet individual patient needs and owner abilities, circumstances, and treatment their observations to the veterinary team. Routine goals. Recommendations for DM monitoring physical examinations and laboratory testing are also in dogs and cats are typically based on expert critical and present opportunities to discuss progress, advice and experience, and published consen- sus guidelines are available.5 Elimination of troubleshoot problems, and assess quality of life. clinical signs of DM is an acceptable and Restoring and maintaining patient quality of life is a achievable goal for most patients, but various paramount concern of most owners 1,2 and should be a monitoring strategies can be used to achieve foundational goal of any monitoring strategy. DM = diabetes mellitus

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acceptable glycemia. Interventions should be per- TABLE 1 formed frequently enough to be effective but not so often that they are impractical or inconvenient for DIABETES MELLITUS MONITORING METHODS the owner.

Monitoring Methods Method Monitoring Test/ Information Monitoring DM involves several direct and indi- Procedure Provided rect methods for assessing glycemic control (Table 1). Direct monitoring uses a quantitative method Direct BG curve Quantitative BG IGM concentration to determine blood glucose (BG; eg, spot or Spot BG determination random BG sampling, BG curve, interstitial glucose monitoring [IGM]). Indirect monitoring Objective HbA1c Retrospective evaluates a subjective (eg, physical examination indirect Serum fructosamine information about BG Urine glucose concentration findings, clinical signs) or objective (eg, quantita- measurement tive measurements of hemoglobin A1c [HbA1c] or fructosamine) parameter influenced by BG rather Subjective Clinical signs Glycemic control inferred than glucose itself. Monitoring for the typical DM indirect Physical examination from history and physical patient should incorporate several methods, each examination with advantages and disadvantages (Table 2).

Assessment of Clinical Signs Polydipsia and polyuria are commonly observed BENEFITS OF MONITORING FOR CLINICAL SIGNS clinical signs of DM that are directly related to the magnitude of hyperglycemia but are of limited The usefulness of monitoring for clinical signs caused by sensitivity and specificity. Hyperglycemia results hyperglycemia is 2-fold: in plasma hypertonicity, which stimulates thirst h A significant disturbance in BG can be inferred from the persistence and promotes volume loss via osmotic diuresis and or emergence of clinical signs during treatment (the renal threshold glucosuria once the renal threshold for glucose for glucose is ≈200 mg/dL in dogs and ≈250 mg/dL in cats).5 reabsorption is exceeded. h Evidence shows a positive correlation between objective measures (ie, serum fructosamine and mean 8-hour BG concentration) and Appetite, body weight, and body condition can also owner assessment of control based on clinical signs.25 provide clues to glycemic control. Appetite persists in most diabetic dogs and cats, but body weight and Careful, frequent evaluation of clinical signs is an important part of condition are abnormal in many patients at the time monitoring BG and protecting overall health.25 DM is a primary cause of cataracts in dogs and a cause of peripheral neuropathy in dogs and of diagnosis; they may be improved through insulin cats.26,27 Thus, signs of these conditions and other common diabetic therapy and glycemic control. Poor glycemic control complications or concurrent disorders (eg, pancreatitis, renal failure, should be suspected if a patient’s weight/condition endocrinopathy, neoplasia) should be included in monitoring.26-28 does not improve or begins to decline during ther- apy. The monitoring strategy must detect deviations from a patient’s normal condition (see Benefits of Monitoring for Clinical Signs). Owners should be made aware of signs of poor glycemic control and BG = blood glucose instructed to observe water consumption, voiding DM = diabetes mellitus habits, and appetite, along with body condition, HbA1c = hemoglobin A1c weight, and overall health. Concerning trends or IGM = interstitial glucose monitoring indicators should be shared with the clinician.

28 cliniciansbrief.com November 2019 TABLE 2

ADVANTAGES & DISADVANTAGES OF DIABETES MELLITUS MONITORING METHODS

Monitoring Method Advantages Disadvantages

ASSESSMENT OF Easy to use frequently Subjective; interpretation vulnerable to bias/ CLINICAL SIGNS Can correlate at-home and in-clinic observations expectations Involves owner in pet’s care Chronic, mild/moderate BG disturbances may be Absence of signs associated with improved quality missed. of life

GLYCATED PROTEIN Provides time-averaged BG information Information is retrospective. MEASUREMENT Monitoring is periodic; requires only a single blood Serial sampling is more helpful than a single test sample result. Reliable commercial assays available for HbA1c and Precise target ranges/therapeutic endpoints are fructosamine undefined. Frequent testing increases cost to owners. Patient factors/concurrent disorders influence results.

Fructosamine Reflects average BG for ≈2 weeks preceding test Does not reflect long-term changes in BG status Does not correlate well with other glycemic assess- ments in some patients

HbA1c Small volume sample required (several drops of blood) Less sensitive to short-term changes in BG Reflects average BG for 70 days (cats) or 120 days (dogs) Can be influenced by factors that affect Hb concen- preceding test tration/turnover

BG MEASUREMENT Provides pharmacodynamic information about response Normal biologic variability may have substantial to insulin impact on results. Immediate, real-time measurement of BG Substantial cost

BG curve Traditional, familiar technique Time consuming; practical considerations limit time Uses simple, reliable technology (glucometer) period over which curve can be performed. Can be performed in the clinic or at home Requires multiple blood samples May not be predictive of future insulin needs

IGM (flash or Provides timely information about insulin action Changes in interstitial glucose lag behind changes in continuous) Provides real-time and retrospective data BG. Well tolerated; suitable for at-home use No approved veterinary IGM units; some manufactur- Daily data can be monitored/collected over several ers may not make technology/equipment available weeks. to clinicians.

Spot BG measurement Useful for documenting hypoglycemia Randomly timed BG measurements have little value (capillary or venous for patient assessment or guiding therapy. blood sample)

URINE GLUCOSE Allows for simultaneous testing for urine glucose and Results are semiquantitative and lag behind blood MONITORING ketones changes. May be only option for home testing for some owners Glucosuria does not correlate closely with BG. Samples may be difficult to obtain for some owners.

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Urine Monitoring Fructosamine values represent the concentrations Urine testing for glucose and ketones in DM is of several glycated serum proteins, but glycated used to detect changes in health status before clin- albumin makes up the largest portion.7 In dogs ical signs appear. Abrupt changes in the magni- and cats, fructosamine concentration is frequently tude of glucosuria or emergence of ketonuria can used to monitor DM and is interpreted to reflect signal a recent disruption in glycemic control, but average glycemia over the previous 2 weeks, which this advantage may not be realized in practice, as is the approximate lifespan of serum albumin. outward clinical signs often precede detection of HbA1c is a specific glycated hemoglobin moiety altered urine glucose or ketone concentrations in used extensively for monitoring glycemia in urine. In addition, urine testing can have several humans with DM but is used less frequently in drawbacks (eg, difficulty in obtaining a sample for veterinary medicine. Due to hemoglobin’s longer testing, leading to poor compliance).6 Overall, this serum lifetime, HbA1c levels reflect average serum method is not recommended for DM monitoring; it glucose over the erythrocyte lifespan in circula- may be useful in some circumstances but must be tion (dogs, ≤120 days; cats, ≈70 days).8 Although interpreted in context of other findings.6 HbA1c represents glycemia over a substantially longer time than fructosamine, acute, short-term Glycated Proteins disruptions in glycemic control affect fruc- Proteins exposed to glucose are altered via a non- tosamine sooner than HbA1c (see Drawbacks of enzymatic chemical reaction. The concentration of Glycated Protein Monitoring). A reduction in these glycated proteins in blood increases with the fructosamine and HbA1c concentrations is circulating BG concentration. Because glycated expected with successful insulin therapy.7,9 proteins are metabolized in the same manner as nonglycated proteins, their concentration in the Clinicians have traditionally relied on fruc- circulation reflects the average BG over the life- tosamine measurement rather than other moieties span of the parent protein. Serum fructosamine partly due to the widespread commercial availabil- and HbA1c are the major glycated proteins in dogs ity of fructosamine assays. However, recent stud- and cats; monitoring these blood concentrations ies have underscored the possible advantage of can provide insight about glycemic control and HbA1c for assessing glycemic control in dogs,10-13 response to insulin. and commercial assays are available for assessing canine and feline HbA1c.

Blood Glucose Direct determination of BG is the gold standard for immediate and real-time assessment of glyce- DRAWBACKS OF GLYCATED mia. In diabetic patients, BG monitoring over time PROTEIN MONITORING reflects pharmacodynamic actions of insulin and Medical conditions that alter concentrations of the can provide information about onset, peak activ- parent protein also affect the glycated versions. ity, and duration of action, as well as its overall Fructosamine reduction occurs in nondiabetic dogs with effectiveness in controlling glycemia. The BG hypoproteinemia or hypoalbuminemia and in those with curve has been the traditional approach used to hyperlipidemia and/or azotemia.29 Fructosamine is also document patient insulin response, but IGM has reduced in cats as a consequence of increased protein turnover associated with concurrent hyperthyroidism,30 become more commonplace. Randomly timed, sin- although it may remain within the reference range.31 Many gle determinations of BG concentration (ie, spot of the conditions affecting fructosamine also affect HbA1c, measurement) have little interpretive value and but HbA1c concentration is also altered by anemia and are not recommended when making decisions other conditions that influence RBC turnover.32 about insulin dose.

30 cliniciansbrief.com November 2019 The Blood Glucose Curve This method involves sampling and testing every INTERSTITIAL GLUCOSE 1 to 2 hours over a defined time (usually 12 hours MONITORING SYSTEMS but sometimes longer) to plot BG, typically using IGM has been used in veterinary medicine for >15 years.33 a portable glucometer. Venous or capillary blood Several systems studied have proven useful in dogs samples from various sites (eg, small vein, ear tip, and cats.34 Advances in technology have rendered paw pad) are obtained manually using a needle IGM systems more user friendly and better suited for or lancet. The number of points on the curve is veterinary applications. A newer FGM system has shown determined by the sampling frequency. The BG promise in veterinary medicine, although published curve is most often performed in clinic, but some information is limited to a single study.35 All commercial clinicians recommend owners learn to do it at IGM systems involve similar components and operating home. A review of the background, method, and principles.15 The basic unit consists of a disposable sensor interpretation of the BG curve is available.14 that combines a serum chemical detection system with a transmitter and receiver that collect, store, and display Interstitial Glucose Monitoring BG data. A stylet introduces the sensor through the skin and positions the tip to contact the interstitial fluid. The IGM allows for measurement of glucose concentra- body of the sensor, which contains the transmitter, is tion in interstitial fluid over days to weeks.15 affixed to shaved skin using a mild adhesive (Figure 1). IGM includes both continuous and flash glucose An incorporated chemical reaction platform metabolizes monitoring (FGM) methods. Continuous glucose interstitial glucose to generate an electrical signal that is monitoring automatically displays each glucose proportional to its concentration.15 A description of the measurement for users in real time and can inte- use of an FGM device in small animals is available.36 grate with insulin pump systems to adjust insulin dosing, whereas FGM displays a single value result only when the sensor is interrogated by the reader (see Interstitial Glucose Monitoring Systems). IGM provides values for glucose that differ from those of capillary or venous blood.16 The gradient between blood and interstitial glucose, which can range from 20% to 110%,16 is greatest when large fluctuations in BG (increasing or decreasing) occur and there is a lag (minutes) before the 2 compartments equili- brate. Thus, IGM may underreport rapid changes in BG, which is particularly important when there is risk for development of hypoglycemia. d FIGURE 1 A sensor unit from a flash device adhered to the skin of a diabetic cat. A manufacturer-provided device easily Monitoring performed by pet owners is a viable applies the small sensor unit (35-mm diameter × 5-mm height) to the shaved area. The sensor uses a flexible filament in con- way for the clinician to obtain BG information.17,18 tact with the interstitial fluid to measure BG every 60 seconds In a study, ≈85% of owners were successful with and data storage capacity to record BG data. Wireless technol- long-term home BG monitoring that required ogy transfers BG data stored in the sensor unit to a handheld frequent blood sampling to produce curves.19 reader unit. Anecdotal reports indicate owners and clinicians BG = blood glucose are willing to use IGM to perform at-home moni- DM = diabetes mellitus toring; this is especially true when an FGM device FGM = flash glucose monitoring is used, as these systems do not require frequent HbA1c = hemoglobin A1c calibration and data can be easily retrieved and IGM = interstitial glucose monitoring analyzed. A particular advantage of FGM systems

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is that daily glycemic data can help facilitate tic decisions. In practice, however, these are very dif- treatment to achieve clinical goals rather than ferent approaches to managing glycemia (Figure 2). just elimination of clinical signs. For example, insulin treatment can be adjusted more frequently Monitoring BG in veterinary patients generally based on glycemic data and metabolic targets serves to assess the larger picture of insulin (eg, desired range for average daily glucose). response and BG control over the day rather than as a guide for day-to-day changes in therapy. Dose Interventional vs Dose Monitoring monitoring can be useful and provide helpful When considering methods of glucose monitoring, it information, but the use of interventional monitor- is worth drawing distinctions between BG monitor- ing should be considered cautiously. Although ing performed to determine a patient’s global some pet owners may be interested in and eager to response to a particular dose of insulin (ie, dose attempt interventional monitoring and make insu- monitoring) and monitoring performed to deter- lin adjustments, the author does not recommend it, mine whether a patient’s immediate glycemic as there has been little evidence to show that the status requires correction (ie, interventional effort and expense actually improve long-term out- monitoring). Both can be accomplished through comes or reduce complications, and the very strin- available techniques, have the same advantages and gent targets for BG control involve increased risk disadvantages, and can be used in making therapeu- for hypoglycemic events in human and, probably,

350

300 A

250 L 200 150

100

50

0 0 4 8 12 16 20 24

d FIGURE 2 Effects of different monitoring strategies on the BG curve. The red line shows a theoretical BG curve following an insulin injection at the 0-hour mark. Within 6 hours of injection, BG returned to the preinsulin level. At this point (A), no action occurs if the dose monitoring strategy is used. However, if the interventional monitoring strategy is used, an additional insulin injection is indicated, as BG exceeds the desired target range (≤250 mg/dL). The subsequent response (gray line) brings BG into an acceptable range. At the 12-hour mark (B), the patient with dose monitoring (red line) received a scheduled second insulin injection, but the patient with interventional monitoring received no insulin, as BG values were in the target range. Without additional intervention, both patient curves were similar (black line) for the remainder of the day. Adopting a strict interventional monitoring strategy requires additional insulin be provided at the 16-hour mark when BG again exceeded the target range.

32 cliniciansbrief.com November 2019 veterinary patients. Studies addressing these con- experimental conditions can vary from 15% to cerns are limited. In a small group of cats receiving 50% day to day.21 Variability is typically greater in at-home monitoring to achieve tight BG control, clinical patients,22 with inconsistent or unpredict- complication rate was low,20 but constant care and able changes in glycemia even after administration anxiety regarding hypoglycemia are common con- of equivalent doses of the same insulin. Numerous cerns among pet owners and chronic or recurrent factors, including the patient’s emotional state (eg, hypoglycemia can lead to increased patient mor- stress or anxiety), exercise, body temperature, and bidity and poor quality of life.1,2 Some clinicians comorbidities, among others, may contribute to use a modified approach to interventional monitor- variability.23 ing described above by having owners check BG immediately before an insulin dose and use the The veterinary literature contains examples of the information to modify the dose as necessary. An effect of biologic variability on BG curve data. In a advantage of this approach is the opportunity to study, dogs receiving the same insulin type and reduce the likelihood of hypoglycemia, but the cli- dose showed marked variability in routinely deter- nician must provide the owner with clear goals and mined BG curve parameters, including minimum, guidelines for making dose decisions. maximum, and mean BG concentrations and time to nadir, on 12-hour BG curves obtained 24 hours Regardless of the method used to obtain a BG apart.24 In that study, curve analysis resulted in a curve, comparison with other measures used to different insulin treatment recommendation in assess BG control (eg, clinical evaluation, markers nearly 45% of paired curves and treatment recom- of long-term glycemic control) can help validate mendations were frequently opposite (ie, one curve results. The BG curve is especially helpful in detect- of the pair indicated a need for a dose increase and ing hypoglycemic events during testing. Hypogly- the other indicated a need for a dose decrease). cemia typically reflects an excess of insulin and should prompt dose reduction. Curve analysis can Conclusion also demonstrate persistent hyperglycemia, which No single monitoring tool or combination has been is consistent with poor glycemic control. Trouble- shown to provide significant, measurable advantag- shooting persistent hyperglycemia is more difficult es in diabetic dogs or cats. Reliance on a single tool than troubleshooting hypoglycemia, as the former is discouraged. Effective monitoring should incorpo- can have numerous causes (eg, poor compliance, rate several methods that assess different aspects of problems with insulin administration, under- glycemic control. A flexible and practical monitoring dosing, insulin resistance). program that aims to provide objective information while balancing patient and owner needs can engage A major limitation of the BG curve is imposed by the pet owner as a primary caregiver, enhance biologic variability that impacts day-to-day insulin compliance, and strengthen the clinician–pet owner action. Depending on insulin type and formulation relationship. n BG = blood glucose used, absorption and activity in humans under

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34 cliniciansbrief.com November 2019